Human Immunology. 2014 July; 75(7): 621-628.
Low density lipoprotein promotes human naïve T cell differentiation to Th1 cells
Amy H. Newton, Stephen H. Benedict
Department of Molecular Biosciences, University of Kansas, Lawrence, KS
Oxidized LDL (oxLDL) in the arterial wall and its incorporation into foam cells leads to inflammation and nucleation of atherosclerotic plaque; this is opposed by HDL. OxLDL and HDL regulate activation of macrophages and endothelial cells, and study of T cell participation has been limited to mature, differentiated cells such as Th1 cells, which perpetuate atherogenesis by promoting cell-mediated responses and inflammation. Immature naïve T cells, just emerged from the thymus, have remained largely unstudied. We hypothesized that LDL and HDL provide selective modulation of immature naïve T cell differentiation and participation in plaque development. In our in vitro model, naïve cells become activated and differentiate to mature effector T cells that are Th1, Th2 or Treg cells. Addition of oxLDL favored differentiation to Th1 cells, reduced Th2 cell activity and prolonged cell survival. In contrast, HDL inhibited T cell proliferation and reduced cell survival. The data suggest a novel mechanism where oxLDL enhances differentiation of human naïve CD4+ T cells to Th1 cells capable of promoting inflammation and plaque progression, and this is opposed by HDL.
KEYWORDS: Atherosclerosis; Human naïve T cells; LDL; T cell differentiation; Th1 cells
Over their lifetime, T cells have the opportunity to respond to hundreds of different stimuli in addition to antigen recognition. Each new microenvironment into which a T cell migrates has the potential to provide a slightly or strongly different array of signals being sensed by the T cell and thus to influence the phenotype and function of that T cell. Hence, in addition to cognate antigen (Ag), there exist over 15 different costimulatory and coinhibitory counter receptor interactions, as well as cytokines, chemokines, adhesion molecules, extracellular matrix proteins, neurotransmitters, endocrine messengers, and others. T cells also express receptors for an array of ambient molecules that can induce signaling. A few examples include pattern recognition receptors and receptors for ambient biochemicals like adenosine, and complement components and lipoproteins such as LDL and HDL.
Work in the present article addressed two issues relative to changes in the T cell microenvironment. First, the overall goal is to contribute to understanding the effects of different microenvironments on the function and post thymic differentiation of the naïve human CD4+ T cell. These cells exit the thymus in search of cognate antigen. Ag encounter induces cell activation and differentiation to effector and memory cells and the microenvironment where the encounter occurs contributes to cell fate. The second, more specific goal is to define effects on the differentiation process that might be exerted by additional counter receptors or ambient soluble molecules for which the T cell expresses receptors. The question being asked here was whether ambient LDL can influence T cell differentiation to a phenotype consonant with promotion of atherosclerosis. Such a phenotype might be Th1 effector T cells. Since HDL is widely known to oppose oxLDL in atherogenesis, the effects of HDL on the same cell processes were examined as well.
Polarization. It has long been known that control of cell fate during differentiation can be achieved by polarizing cytokines that direct the cell toward, for example Th1 (T helper 1) cells, Th2 cells, or Th17 cells. Polarizing cytokines not only favor differentiation to a particular cell fate as where IFNg favors appearance of Th1 cells but at the same time, diminishes polarization to Th2. It also is known that costimulation through the T cell antigen receptor (TCR) plus the well described costimulatory molecule CD28 leads (without exogenously added cytokines) to differentiation to Th1, and Th2 effector and memory cells, but not to Th17 or Treg cells. We hypothesized that in a selected microenvironment a different costimulatory molecule might exert different effects on differentiation compared with CD28 if no polarizing cytokines were added (1). We determined that T cell resident ICAM-1, could serve as a T cell costimulatory receptor (2). We then observed that costimulation through ICAM-1 caused differentiation to Th1 but not Th2 or Th17, and surprisingly to Treg cells (3-5). This supported the hypothesis and supported the thought that differentiating naïve T cells were capable of responding specifically to their microenvironment during differentiation.
Proatherosclerotic microenvironment. It is probable that T cells do not nucleate plaque but indeed are necessary for expansion and development of the plaque. Tissues enriched in oxidized LDL are known to favor atherosclerotic lesions. We hypothesized that one effect would be that microenvironments rich in oxLDL might favor increase differentiation to Th1, proatherosclerotic T cells. It was also of interest to learn potential effects when HDL enriched the microenvironment since it was logical to envision opposing results. In the present manuscript, our results support the possibility that oxLDL indeed favors atherosclerosis (Table) by tuning differentiation to the Th1 phenotype, opposing appearance of Th2 cells in one microenvironment (CD28 costimulation) and increasing Th17 cells in the other microenvironment (costimulation through ICAM-1). As part of the process, oxLDL favored increased effector T cells (Teff) and diminished differentiation to memory T cells (Tmem) while increasing cell activation and diminishing cell death. Perhaps equally interesting from a therapeutic standpoint were the data suggesting how directly HDL opposed the effects of LDL.
In summary, the present work supports the thought that subtle changes in ambient microenvironment can contribute to fine tuning the T cell differentiation response. The data add the opposing forces of oxLDL and HDL to the list of modulatory molecules that can influence atherogenic differentiation of T cells. Next steps in the progression will be to determine the mechanisms involved, and to identify and test additional known microenvironment components in an attempt to model the events in greater detail.
Table. Effects of adding either oxLDL or HDL to naïve human T cells stimulated either through CD3+CD28 or CD3+ICAM-1. The symbol (–) indicates that the lipoprotein had no effect on the stimulation; é indicates an increase in the parameter due to the added phospholipid; and ê indicates a decrease. Arrows in brackets were not statistically supportable but did exhibit a trend.
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Acknowledgements: This work was supported by the Patricia Watkins Emphysema Research Fund and the Kansas University Diabetes Institute. AHN was supported by a Madison and Lila Self Graduate Fellowship.
Stephen Benedict, Ph.D.
Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave, Lawrence, KS 66045. email@example.com
Present Address: Dr. Amy Newton, Beirne B. Carter Center for Immunology Research, Department of Microbiology, University of Virginia, VA